{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:10:38Z","timestamp":1791835838365,"version":"4.3.4"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T00:00:00Z","timestamp":1664323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Most therapeutics targeting cardiac voltage-gated sodium channels (Nav1.5) attenuate the sodium current (I<jats:sub>Na<\/jats:sub>) conducted through the pore of the protein. Whereas these drugs may be beneficial for disease states associated with gain-of-function (GoF) in Nav1.5, few attempts have been made to therapeutically treat loss-of-function (LoF) conditions. The primary impediment to designing efficacious therapies for LoF is a tendency for drugs to occlude the Nav1.5 central pore. We hypothesized that molecular candidates with a high affinity for the fenestrations would potentially reduce pore block.<\/jats:p><jats:p><jats:bold>Methods and Results:<\/jats:bold> Virtual docking was performed on 21 compounds, selected based on their affinity for the fenestrations in Nav1.5, which included a class of sulfonamides and carboxamides we identify as <jats:italic>ARumenamide (AR)<\/jats:italic>. Six <jats:italic>ARs<\/jats:italic>, AR-051, AR-189, AR-674, AR-802, AR-807 and AR-811, were further docked against Nav1.5 built on NavAb and rNav1.5. Based on the virtual docking results, these particular <jats:italic>AR<\/jats:italic>s have a high affinity for Domain III-IV and Domain VI-I fenestrations. Upon functional characterization, a trend was observed in the effects of the six <jats:italic>ARs<\/jats:italic> on I<jats:sub>Na<\/jats:sub>. An inverse correlation was established between the aromaticity of the <jats:italic>AR<\/jats:italic>\u2019s functional moieties and compound block. Due to its aromaticity, AR-811 blocked I<jats:sub>Na<\/jats:sub> the least compared with other aromatic <jats:italic>ARs<\/jats:italic>, which also decelerated fast inactivation onset. AR-674, with its aliphatic functional group, significantly suppresses I<jats:sub>Na<\/jats:sub> and enhances use-dependence in Nav1.5. AR-802 and AR-811, in particular, decelerated fast inactivation kinetics in the most common Brugada Syndrome Type 1 and Long-QT Syndrome Type 3 mutant, E1784K, without affecting peak or persistent I<jats:sub>Na<\/jats:sub>.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Our hypothesis that LoF in Nav1.5 may be therapeutically treated was supported by the discovery of <jats:italic>ARs<\/jats:italic>, which appear to preferentially block the fenestrations. <jats:italic>ARs<\/jats:italic> with aromatic functional groups as opposed to aliphatic groups efficaciously maintained Nav1.5 availability. We predict that these bulkier side groups may have a higher affinity for the hydrophobic milieu of the fenestrations, remaining there rather than in the central pore of the channel. Future refinements of <jats:italic>AR<\/jats:italic> compound structures and additional validation by molecular dynamic simulations and screening against more Brugada variants will further support their potential benefits in treating certain LoF cardiac arrhythmias.<\/jats:p>","DOI":"10.3389\/fphar.2022.976903","type":"journal-article","created":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T07:31:48Z","timestamp":1664350308000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["ARumenamides: A novel class of potential antiarrhythmic compounds"],"prefix":"10.3389","volume":"13","author":[{"given":"Mena","family":"Abdelsayed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Page","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"Ruben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3643","DOI":"10.1038\/s41598-018-22033-1","article-title":"The efficacy of Ranolazine on E1784K is altered by temperature and calcium","volume":"8","author":"Abdelsayed","year":"2018","journal-title":"Sci. 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